Tobacco use is the leading cause of preventable morbidity and mortality in the U.S. Identifying effective medications for the treatment of tobacco dependence remains a high priority as the vast majority of smokers fail to maintain long-term abstinence even with FDA approved pharmacotherapies. One promising, yet relatively unexplored avenue for medication development for smoking cessation, are medications which target stress-reactivity. Several lines of evidence suggest that stress is a primary mediator of smoking maintenance and relapse. Preclinical research demonstrates that noradrenergic pathways are involved in stress-induced reinstatement to nicotine, as well as nicotine-related reinforcement and withdrawal, and that their manipulation may be of potential therapeutic benefit for smoking cessation. Modeling the effect of stress on smoking behavior, we have demonstrated that 3mg/day guanfacine, an alpha2a noradrenergic agonist, compared to placebo was well tolerated, robustly increased the ability to resist smoking, and decreased tobacco craving, ad-lib smoking, and smoking-related reinforcement. During an fMRI session, guanfacine increased activity in regions associated with improved attention and self-control. Guanfacine also reduced smoking and improved retention during a subsequent brief treatment period. Overall, our results point to guanfacine as a potential pharmacotherapy for stress-precipitated smoking relapse with benefit in the clinical setting. The primary goal of this project is to translate our preclinical, human laboratory, imaging, and clinical outcome findings with guanfacine and conduct the first single-site, proof-of-concept, Phase II clinical trial evaluating the efficacy of guanfacine for smoking cessation. Using a double-blind, placebo-controlled, dose- ranging parallel group design, we plan to [[[ randomize 375 adult daily smokers to guanfacine (3mg/day, 2mg/day, or placebo, n=125 per cell) ]]] combined with brief behavioral support for an 8-week treatment period to evaluate which doses of guanfacine are efficacious in increasing prolonging smoking abstinence while minimizing adverse events. Participants will then be followed for a 6-month period from the end of treatment to assess the durability of treatment effects. In addition to standard smoking cessation outcomes, we will evaluate craving, withdrawal, perceived stress, cognitive function, and smoking-related reinforcement as potential mechanisms underlying medication effects. Positive findings will provide the data necessary to expand this investigation to Phase III testing.